PROJECT SUMMARY/ABSTRACT Improving neurodevelopmental outcomes for the nearly 60,000 preterm infants born each year is a major goal for neonatal care providers. A subset of these infants sustain a major intraventricular hemorrhage (IVH) resulting in an increased incidence of developmental delay. Moreover, almost one-third of preterm infants with normal head ultrasounds also develop cognitive delay. Although a variety of treatment strategies have been evaluated, no specific treatment has been identified to improve neurodevelopmental outcomes in preterm infants. One potential therapy involves administering erythropoiesis stimulating agents (ESAs) such as erythropoietin (Epo) and Darbepoetin (Darbe, a longer acting ESA). Initially investigated for their effects on decreasing transfusions in preterm infants, ESAs have been shown to be protective in the developing brain, and thus possibly beneficial for very premature infants who are at risk for IVH, hypoxic-ischemic injury, and developmental delay. We previously evaluated both hematologic and neurodevelopmental outcomes at 18-22 months corrected age in a multicenter trial of 99 preterm infants randomized to receive Epo, Darbe, or placebo through 35 weeks postmenstrual age. ESA-treated infants received fewer transfusions and were exposed to fewer donors. At 18-22 months ESA-treated infants had significantly higher cognitive scores and lower rates of neurodevelopmental impairment, including no cerebral palsy. At 4 and 6 years of age, higher cognitive and executive function scores were measured in ESA compared to placebo recipients. Darbe recipients had improved executive function compared to Epo recipients while receiving one-third the doses, thus providing evidence that Darbe might provide even greater benefit than Epo for preterm infants. This proposal addresses our long-term goal of developing effective treatment strategies to improve outcomes in preterm infants. Understanding the impact of increased hematocrit and decreased transfusions in addition to the non-hematopoietic mechanisms of ESAs is necessary to achieve optimal developmental outcomes. Applying the experience and rigor of the Neonatal Research Network infrastructure in performing randomized placebo controlled trials, our specific aims are to evaluate the effect of Darbe administered in the first 10 weeks of life to preterm infants born at 23 to 28 completed weeks gestational age on (1) donor and transfusion requirements and measures of red cell mass, and (2) neurocognitive outcomes at 22-26 months adjusted age. Hematocrit, transfusions, and donor exposures will be collected during hospitalization, and neurodevelopmental outcome will be assessed through comprehensive testing at 22-26 months (Bayley Scales of Infant Development III, executive function, and neurologic exam). If outcomes of the previous study are confirmed, the use of Darbe could become standard of care and significantly improve the lives of thousands of preterm infants.